Impact of AI-guided multi-analyte precision oncology–based platform on clinical outcomes in treatment-refractory pan-cancer patients.

e15121 Background: Refractory solid tumors exhibit profound molecular and functional heterogeneity, frequently requiring repeated treatment modifications after failure of standard therapies. Single-parameter testing is insufficient to guide such iterative decision-making. Comprehensive, integrated tumor profiling may enable rational, personalized treatment iterations and sustain clinical benefit across successive lines of therapy. Methods: Patients with refractory solid tumors underwent integrated EXACTA profiling encompassing genomic alterations, gene expression, immunohistochemistry, immune biomarkers, and in-vitro chemosensitivity assays. Actionable alterations and targetable pathways were identified to guide personalized therapy across successive lines. Progression-free survival (PFS) was assessed for each EXACTA-guided line. PFS ratios (PFSr) were calculated relative to the immediately preceding line, with modified PFSr (mPFSr) applied to adjust for potential false-positive and false-negative signals. The best mPFSr per patient was used to assess clinical benefit from iterative EXACTA-guided therapy. Results: EXACTA based profiling identified a highly heterogeneous yet clinically actionable genomic landscape, with recurrent alterations in PIK3CA , EGFR , ERBB2 , KRAS , BRAF , CCND1 , and BRCA2 supporting precision-guided therapy. PD-L1-stratified analysis revealed enrichment of truncating APC mutations in PD-L1-positive tumors, whereas CTNNB1 alterations were confined to PD-L1-negative tumors. Sequential EXACTA-guided therapies derived from a single comprehensive profiling event resulted in clinically meaningful benefit across multiple treatment lines. Based on best modified progression-free survival ratios (mPFSr) achieved per patient, 60.74% of patients demonstrated mPFSr > 1.5, 68.14% achieved mPFSr > 1.3, and 68.8% achieved mPFSr > 1.25. Line-wise distributions of mPFSr, including the proportion of patients achieving mPFSr > 1.3 at each EXACTA-guided treatment line, are summarized in the Table 1. Conclusions: Integrated EXACTA profiling revealed distinct tumor biology and enabled optimized treatment strategies. Mutual exclusivity of CTNNB1 alterations in PD-L1–negative tumors and enrichment of truncating APC mutations support β-catenin–TCF4–mediated PD-L1 regulation. In refractory solid tumors, a single EXACTA profiling enabled iterative, biology-guided therapy with sustained benefit. PFS ratio gains beyond the first EXACTA-guided line demonstrate the durable clinical utility of integrated profiling, supporting improved outcomes despite disease progression. Durability of Clinical Benefit Across EXACTA-Guided Lines. mPFSr from Exacta Lines >1.5 >1.3 >1.25 L2/L1 30.43% 39.13% 39.13% L3/L2 22.22% 25.92% 22.22% L4/L3 50% 50% 50%